The extracellular matrix plays an active role in muscle regeneration

Abstract

In urodele amphibians like the newt, skeletal muscle provides a reservoir for uncommitted stem‐like blastema cells that participate in the regeneration of the lost structure. Using 3D immunohistochemical analyses we found dynamic expression of a transitional extracellular matrix (ECM) rich in hyaluronic acid (HA), tenascin‐C (TN) and fibronectin (FN) around skeletal muscle. To test the hypothesis that the ECM plays key instructive roles early in blastema formation, we investigated the behavior of muscle cells under defined culture conditions using time‐lapse microscopy. Our results revealed that distinct components of the early transitional matrix supported myoblast migration and inhibited fusion (HA and TN) whereas ECM expressed around differentiating muscle induced both proliferation and fusion (FN and laminin). In addition, we developed silicone elastomer substrates with a tunable stiffness that can mimic the transverse stiffness of newt skeletal muscle and blastema (17 kPa and 14 kPa, respectively). By combining defined ECM components with a substrate of appropriate native stiffness, we aim to control the behavior of muscle‐derived cells with high precision. The establishment of a physiologically relevant environment and its controlled manipulation in vitro will provide new insights into the control of the differentiated state of the cell. Funded by NIH, Searle Foundation.Grant Funding Source: NIH, Searle Foundation